Original Article
Hemodynamic effects of the dipeptidyl peptidase-4
inhibitor linagliptin with renin^angiotensin system
inhibitors in type 2 diabetic patients with albuminuria
Mark E. Cooper a, Vlado Perkovic b, Per-Henrik Groop a,c,d,e, Berthold Hocher f,g, Uwe Hehnke h,
Thomas Meinicke i, Audrey Koitka-Weber a,h,j, Sandra van der Walt h, and Maximilian von Eynatten h
Downloaded from https://journals.lww.com/jhypertension by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3GqhOzspyl8xKMLws3Bk+kEe3ESWDqBLaNBtkTKVEFDg= on 03/06/2020
Objective: Concomitant treatment with angiotensin-
converting enzyme (ACE) inhibitors and dipeptidyl
peptidase-4 (DPP-4) inhibitors is increasingly common.
Pharmacological studies have suggested a potential
adverse drug interaction between ACE inhibitors and DPP-
4 inhibitors resulting in unfavorable hemodynamic
changes; very few studies have examined such an
interaction between angiotensin II receptor blockers (ARBs)
and DPP-4 inhibitors. We investigated blood pressure (BP)
and heart rate (HR) during treatment with the DPP-4
inhibitor linagliptin in individuals receiving either ACE
inhibitors or ARBs in the MARLINA-T2D trial.
Methods: In this study, 360 individuals with type 2 diabetes
and albuminuria receiving unchanged doses of ACE inhibitors
or ARBs were randomized to linagliptin or placebo. Twenty-
four-hour ambulatory BP monitoring, an exploratory
endpoint, was conducted at baseline and after 24 weeks.
Results: Ambulatory BP monitoring data were available for
208 individuals (linagliptin: n ¼ 111; placebo: n ¼ 97).
Baseline mean  SD 24-h SBP and DBP were
132.5  12.4 mmHg and 75.9  9.4 mmHg, respectively;
mean 24-h HR was 76.3  10.1 bpm. At week 24, no
overall effect of the DPP-4 inhibitor versus placebo was
seen on mean 24-h SBP, DBP, or HR. Furthermore, in the
subgroups receiving either an ACE inhibitor or an ARB, no
effect on these hemodynamic parameters was seen as a
result of concomitant DPP-4 inhibitor treatment.
Conclusion: Adding linagliptin to treatment with ACE
inhibitors or ARBs was not associated with any
hemodynamic changes, supporting their concomitant use
in individuals with type 2 diabetes and albuminuria.
Keywords: ambulatory, angiotensin-converting enzyme
inhibitors, AT1 antagonists, blood pressure, blood pressure
monitoring, dipeptidyl-peptidase IV inhibitors, drug
interaction, heart rate
Abbreviations: ABPM, ambulatory blood pressure
monitoring; ACE, angiotensin-converting enzyme; ARB,
angiotensin II receptor blocker; CI, confidence interval;
DPP-4, dipeptidyl peptidase-4; eGFR, estimated glomerular
filtration rate; MedDRA, Medical Dictionary for Regulatory
Activities; NPY, neuropeptide Y; T2D, type 2 diabetes;
UACR, urinary albumin-to-creatinine ratio
1294 www.jhypertension.com
INTRODUCTION
D
iabetes affects an estimated 30 million people in
the United States [1] and 415 million individuals
globally [2], most commonly type 2 diabetes (T2D)
(90–95% of cases [1]). T2D is frequently associated with
conditions such as hypertension, chronic kidney disease
and heart failure [3–5], which are often treated with drugs
that interrupt the renin–angiotensin system (RAS), includ-
ing angiotensin-converting enzyme (ACE) inhibitors or
angiotensin II receptor blockers (ARBs).
Consequently, as a result of the epidemic of T2D
and its associated comorbidities, a large number of
individuals currently receive concomitant treatment
with RAS blockers such as ACE inhibitors and dipeptidyl
peptidase-4 (DPP-4) inhibitors, a class of frequently
prescribed oral glucose-lowering drugs [6]. DPP-4 inhib-
itors reduce blood glucose levels mainly by inhibiting
enzymatic degradation of glucagon-like peptide-1, a
major substrate of DPP-4 that stimulates glucose-depen-
dent insulin secretion. However, DPP-4 also has other
peptide substrates, some of which are vasoactive such
as substance P. Furthermore, DPP-4 is largely responsible
Journal of Hypertension 2019, 37:1294–1300
a
Department of Diabetes, Central Clinical School, Monash University, Melbourne,
Victoria, bThe George Institute for Global Health, University of New South Wales,
Sydney, New South Wales, Australia, cFolkhälsan Institute of Genetics, Folkhälsan
Research Center, Biomedicum Helsinki, dAbdominal Center Nephrology, University of
Helsinki and Helsinki University Hospital, eResearch Programs Unit, Diabetes and
Obesity, University of Helsinki, Helsinki, Finland, fFifth Department of Medicine
(Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim,
University of Heidelberg, Heidelberg, Germany, gDepartment of Nephrology, The
First Affiliated Hospital of Jinan University, Guangzhou, China, hBoehringer Ingelheim
International GmbH, Ingelheim, iBoehringer Ingelheim International GmbH, Biberach
and jDivision of Nephrology, Department of Medicine, Würzburg, University Clinic,
Würzburg, Germany
Correspondence to Mark E. Cooper, Department of Diabetes, Central Clinical School,
Monash University, 99 Commercial Road, Melbourne 3004, VIC, Australia. Tel: +61 3
99030006; e-mail: mark.cooper@monash.edu
Received 4 February 2018 Accepted 27 November 2018
J Hypertens 37:1294–1300 Copyright ß 2019 The Author(s). Published by Wolters
Kluwer Health, Inc. This is an open-access article distributed under the terms of the
Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-
NC-ND), where it is permissible to download and share the work provided it is properly
cited. The work cannot be changed in any way or used commercially without
permission from the journal.
DOI:10.1097/HJH.0000000000002032
Volume 37  Number 6  June 2019
 Hemodynamics of linagliptin/renin–angiotensin system blockers
for the inactivation of substance P when ACE is inhibited
[7,8].
An adverse hemodynamic interaction between DPP-4
inhibitors and ACE inhibitors has been postulated based on
pharmacological studies in which increases in blood pres-
sure (BP) and heart rate (HR) manifested during concomi-
tant treatment with ACE inhibitors and experimental (P32/
98) or licensed DPP-4 inhibitors (sitagliptin) [9,10]. The
need for further studies in this area was highlighted recently
[11]. Furthermore, there appears to be little data on potential
hemodynamic interactions between DPP-4 inhibitors and
ARBs. Consequently, we explored the potential hemody-
namic effects of another licensed DPP-4 inhibitor, linaglip-
tin, in individuals with T2D and renal disease as reflected by
the presence of microalbuminuria or macroalbuminuria
who were receiving concomitant treatment with ACE inhib-
itors or ARBs.
METHODS
This was a prespecified, exploratory analysis of a 24-week,
randomized, double-blind, placebo-controlled, multina-
tional clinical trial of linagliptin conducted in individuals
with T2D and renal dysfunction (MARLINA-T2D; Clinical-
Trials.gov: NCT01792518).
MARLINA-T2D was designed to investigate the glycemic
and albuminuric effects of linagliptin; the full study method-
ology and main results are described in detail elsewhere
[12,13]. In brief, individuals with T2Ds were eligible to
participate if they were aged 18–80 years with glycated
hemoglobin A1c levels of 6.5–10.0%, BMI of 40 kg/m2 or
less, estimated glomerular filtration rate (eGFR) at least
30 ml/min per 1.73 m2, and were either drug-naı̈ve or receiv-
ing up to two oral glucose-lowering drugs and/or basal
insulin. Individuals were also required to have albuminuria,
manifesting as urinary albumin-to-creatinine ratio (UACR) of
30–3000 mg/g, or albuminuria more than 30 mg/l of urine, or
urinary albumin excretion rate more than 30 mg/min clearly
documented in the previous 12 months or detected at
screening. Albuminuria had to be confirmed prior to ran-
domization with a geometric mean UACR of 30–3000 mg/g
from three consecutive morning urine samples collected 14–
16 days before randomization. Eligible individuals must also
have been receiving a stable (unchanged) dose of an ACE
inhibitor or ARB for at least the ten preceding weeks.
Following a two-week placebo run-in period, partici-
pants were randomized to receive double-blind, once-daily
oral treatment with linagliptin 5 mg or placebo for 24
weeks. In an exploratory analysis, changes from baseline
in mean 24-h SBP, mean 24-h DBP, and mean 24-h HR – all
recorded using ambulatory BP monitoring (ABPM) – were
assessed at baseline and after 24 weeks of treatment. These
endpoints were analyzed in the treated set of participants
(those who received at least one dose of study drug) using
an analysis of covariance. ABPM values measured after the
start of glycemic rescue therapy or after a change in anti-
hypertensive treatment were not included in the analysis.
Post-hoc analyses were conducted for changes in ethnic
subgroups (Asian/non-Asian) and changes in the day or
night separately; for the latter, day and night were defined
as 0601–2159 h and 2200–0600 h, respectively.
Journal of Hypertension
Safety analyses were performed as previously described
[13]. Adverse events of relevance to the current analysis
were defined as those in the vascular disorders system
organ class from the Medical Dictionary for Regulatory
Activities (MedDRA) version 18.1, as well as hypersensitiv-
ity reactions (MedDRA 18.1 Standardized MedDRA Query),
and cardiovascular events adjudicated by a blinded, exter-
nal clinical event committee.
RESULTS
Of the 360 participants in the treated set, ABPM data were
available at baseline for 298 individuals (linagliptin:
n ¼ 155; placebo: n ¼ 143). At baseline, mean  SD 24-h
SBP, 24-h DBP, and 24-h HR were 132.7  12.9 mmHg,
75.9  9.1 mmHg and 77.3  10.4 bpm, respectively
(Table 1). These and other mean baseline characteristics
were similar in the 208 participants (linagliptin: n ¼ 111;
placebo: n ¼ 97) with ABPM data at both baseline and week
24 (Table 1).
At week 24, there were no significant placebo-adjusted
changes from baseline in mean 24-h SBP, 24-h DBP, or 24-h
HR in individuals treated with linagliptin (Fig. 1). There was
no significant difference between the predominant ethnic
group (Asians) and other (non-Asian) participants in these
parameters: P values for treatment interaction with race were
0.7035, 0.8149, and 0.4196 for mean change from baseline in
24-h SBP, 24-h DBP, and 24-h HR respectively (Fig. S1,
Supplemental Digital Content, http://links.lww.com/HJH/
B54). There was also no significant treatment difference in
changes in mean 24-h SBP, 24-h DBP, or 24-h HR within the
day or night periods separately (Fig. S2, Supplemental Digital
Content, http://links.lww.com/HJH/B54).
Background antihypertensive medication was unchanged
throughout the study in the large majority of participants:
only 7.2 and 5.7% of the linagliptin and placebo groups,
respectively, had a change in dose, and only 9.4 and 8.6%,
respectively, started a new antihypertensive medication.
In subgroups based on the type of RAS blocker received,
the placebo-adjusted change from baseline in mean 24-h SBP
at week 24 with linagliptin was 2.30 mmHg [95% confi-
dence interval (CI) 7.43, 2.84; P ¼ 0.3789] in participants
receiving ACE inhibitors and 0.90 mmHg (95% CI 2.32, 4.11;
P ¼ 0.5825) in those receiving ARBs (Fig. 2). For mean 24-h
DBP, the placebo-adjusted change from baseline at week 24
was 0.61 mmHg (95% CI 3.41, 2.20; P ¼ 0.6712) in par-
ticipants taking ACE inhibitors and 0.20 mmHg (95% CI
1.57, 1.96; P ¼ 0.8260) in those taking ARBs (Fig. 2). The
placebo-adjusted change from baseline in mean 24-h HR at
week 24 was 0.46 bpm (95% CI 3.16, 2.24; P ¼ 0.738) in
participants receiving ACE inhibitors and 1.29 bpm (95% CI
0.40, 2.98; P ¼ 0.135) in those receiving ARBs (Fig. 2).
The overall incidence of adverse events was similar
between the linagliptin and placebo groups, with few
participants experiencing vascular disorders, hypersensitiv-
ity reactions or cardiovascular events (Table 2).
DISCUSSION
In this prespecified exploratory analysis of the MARLINA-
T2D study, treatment with the DPP-4 inhibitor linagliptin
www.jhypertension.com 1295
Cooper et al.

TABLE 1. Baseline demographic and clinical characteristics

Treated seta 24-h ABPM populationb
Linagliptin, n ¼ 182 Placebo, n ¼ 178 Linagliptin, n ¼ 111 Placebo, n ¼ 97
Age (years) 61.0  10.0 60.1  9.3 61.2  9.7 60.7  9.6
Male, n (%) 116 (63.7) 113 (63.5) 74 (66.7) 63 (64.9)
Race, n (%)
Asian 117 (64.3) 122 (68.5) 79 (71.2) 71 (73.2)
White 56 (30.8) 53 (29.8) 29 (26.1) 24 (24.7)
Black/African-American 8 (4.4) 3 (1.7) 2 (1.8) 2 (2.1)
Hawaiian/Pacific Islander 1 (0.5) 0 (0.0) 1 (0.9) 0 (0.0)
BMI (kg/m2) 28.3  4.8 28.6  4.9 27.8  4.5 28.6  4.9
Weight (kg) 78.1  18.6 77.9  19.3 76.4  17.5 77.5  18.4
HbA1c, % (mmol/mol) 7.81  0.87 (61.9  9.5) 7.87  0.88 (62.5  9.6) 7.83  0.80 (n/a) 7.88  0.82 (n/a)
Time since diagnosis of diabetes, n (%)
1 year 11 (6.0) 8 (4.5) 4 (3.6) 3 (3.1)
>1–5 years 26 (14.3) 41 (23.0) 17 (15.3) 23 (23.7)
>5–10 years 47 (25.8) 56 (31.5) 27 (24.3) 32 (33.0)
>10 years 98 (53.8) 73 (41.0) 63 (56.8) 39 (40.2)
eGFR (CKD-EPI, cystatin C) (ml/min per 1.73 m2) 102.8  49.7 94.4  43.3 104.17  52.53 92.32  44.37
eGFR (CKD-EPI, cystatin C) (ml/min per 1.73 m2), n (%)
90 98 (53.8) 88 (49.4) 58 (52.3) 47 (48.5)
60–<90 54 (29.7) 48 (27.0) 35 (31.5) 28 (28.9)
30–<60 25 (13.7) 39 (21.9) 15 (13.5) 20 (20.6)
<30 5 (2.7) 3 (1.7) 3 (2.7) 2 (2.1)
UACR (mg/g) gMean  gCV 120.8  152.9 131.8  165.8 117.1  147.5 150.1  163.9
UACR (mg/g), n (%)
<30 11 (6.0) 10 (5.6) 6 (5.4) 4 (4.1)
30–<300 134 (73.6) 128 (71.9) 85 (76.6) 68 (70.1)
300 35 (19.2) 37 (20.8) 20 (18.0) 25 (25.8)
Missing data 2 (1.1) 3 (1.7) 0 (0) 0 (0)
SBP (mmHg) 135.1  13.8 134.6  13.7 134.5  13.6 134.3  12.9
Mean 24-h SBP (mmHg) 131.8  12.6c 133.7  13.1d 131.6  12.4 133.5  12.3
DBP (mmHg) 77.3  9.0 78.6  8.3 76.0  9.2 79.0  7.6
Mean 24-h DBP (mmHg) 74.8  9.1c 77.0  9.0d 74.4  9.4 77.5  9.2
Heart rate (bpm) 75.0  10.9 75.6  10.9 74.1  11.0 76.1  9.7
Mean 24-h heart rate (bpm) 76.9  10.4c 77.8  10.3d 76.0  10.9 76.6  9.2
Antihypertensive therapy, n (%) 182 (100.0) 178 (100.0) 111 (100.0) 97 (100.0)
ARBs 120 (65.9) 120 (67.4) 81 (73.0) 69 (71.1)
ACE inhibitors 62 (34.1) 58 (32.6) 30 (27.0) 28 (28.9)
Calcium antagonists 79 (43.4) 88 (49.4) 54 (48.6) 50 (51.5)
Diuretics 52 (28.6) 54 (30.3) 29 (26.1) 29 (29.9)
b-Blockers 40 (22.0) 47 (26.4) 25 (22.5) 25 (25.8)
Other 11 (6.0) 15 (8.4) 7 (6.3) 9 (9.3)
Oral glucose-lowering monotherapy, n (%) 66 (36.3) 67 (37.6) 41 (36.9) 35 (36.1)
Metformin 61 (33.5) 64 (36.0) 37 (33.3) 33 (34.0)
Oral glucose-lowering combination therapy without insulin, n (%) 42 (23.1) 48 (27.0) 23 (20.7) 25 (25.8)
Insulin, n (%) 64 (35.2) 49 (27.5) 41 (36.9) 27 (27.8)

Data are mean  SD unless otherwise stated. ABPM, ambulatory blood pressure monitoring; ACE inhibitor, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker;
CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; gCV, geometric coefficient of variation; gMean, geometric mean; HbA1c,
glycated hemoglobin A1c; n/a, not available; UACR, urinary albumin-to-creatinine ratio.
a
All randomized participants who received at least one dose of study drug.
b
All participants in the treated set with ABPM data at both baseline and week 24.
c
n ¼ 155.
d
n ¼ 143.

added to stable doses of ACE inhibitors or ARBs was not
associated with changes in BP or HR in individuals with
T2D and albuminuria.
A potential adverse hemodynamic interaction between
DPP-4 inhibitors and ACE inhibitors was initially reported
from pharmacological studies [9,10]. In the spontaneously
hypertensive rat model, acute administration of an experi-
mental DPP-4 inhibitor (P32/28) increased BP in animals
pretreated with the ACE inhibitor captopril [9]. Conversely,
in a randomized, placebo-controlled, cross-over study in 24
individuals with metabolic syndrome who were pretreated
for 5 days with sitagliptin, a licensed DPP-4 inhibitor, the
hypotensive response to an acute high dose (10 mg) of
enalapril was attenuated, but not to a low dose (5 mg) of
enalapril. Sitagliptin treatment alone led to a mild hypoten-
sive response. Furthermore, only high-dose enalapril
increased HR and plasma norepinephrine concentration
[10]. The authors suggested that the mild hypotensive
response to DPP-4 inhibition might be mediated in part
by the attenuation of substance P metabolism. They further
suggested that during combined high-dose ACE inhibition
and DPP-4 inhibition, activation of the sympathetic nervous
system by substance P and decreased degradation of
neuropeptide Y (NPY)1–36 may offset the decreased

1296 www.jhypertension.com Volume 37  Number 6  June 2019

 Hemodynamics of linagliptin/renin–angiotensin system blockers

FIGURE 1 Change from baseline in mean 24-h SBP, DBP, and heart rate at week 24. Analysis of covariance model includes baseline mean 24-h SBP, baseline log10
(urinary albumin-to-creatinine ratio), baseline glycated hemoglobin A1c as linear covariates and treatment as a fixed effect, yanalysis of covariance model includes baseline
mean 24-h DBP, baseline log10 (urinary albumin-to-creatinine ratio), baseline glycated hemoglobin A1c as linear covariates and treatment as a fixed effect, zanalysis of
covariance model includes baseline mean 24-h heart rate, baseline log10 (urinary albumin-to-creatinine ratio), baseline glycated hemoglobin A1c as linear covariates and
treatment as a fixed effect. CI, confidence interval.

degradation of vasodilatory peptides [10]. The vasodilatory
substance P is normally inactivated via proteolytic cleavage
by ACE in vivo – however, in the absence of ACE activity,
substance P is inactivated by DPP-4 [7,8]. Subsequently, the
same group reported that exogenous substance P increased
sympathetic activity during acute treatment with both enal-
april and sitagliptin in a randomized, double-blind, pla-
cebo-controlled, cross-over study in 12 healthy individuals
[14]. The vasoconstrictive NPY1–36 is inactivated to NPY3–36
by DPP-4. In a study in the spontaneously hypertensive rat
model, sitagliptin had prohypertensive effects that were
mediated by NPY1–36, and the latter was shown to elicit
potent vasoconstriction in the kidneys [15].
There are several possible reasons for the divergent
findings between these previous studies and our observa-
tions on the hemodynamic effects of combined DPP-4 and
ACE inhibition. First, the previous studies only investigated
the acute or short-term treatment effect, whereas individu-
als in the MARLINA-T2D study were treated with the com-
bination of linagliptin and either an ACE inhibitor or ARB
for 24 weeks. It is unclear whether transient initial increases
in BP and HR arising from combined DPP-4 and ACE
inhibition would have clinical relevance in the absence
of long-term changes. Second, unlike the previous studies,
many participants in MARLINA-T2D were receiving other
antihypertensive agents as well as ACE inhibitors, which
may have attenuated increases in BP and HR. For example,
one-quarter of participants were receiving b-blockers. The
antihypertensive polypharmacy seen in MARLINA-T2D is
common in clinical practice, as most individuals with
hypertension require two or more drugs to achieve target
BP, thus highlighting the clinical generalizability of these
findings [16,17]. Third, the increases in BP and HR observed
previously during acute treatment with sitagliptin and enal-
april occurred only with high doses of the latter agent [10]
whereas individuals in our study were treated with lower,
practice-based, ACE inhibitor doses. Fourth, there may be
within-class heterogeneity for interactions between ACE
inhibitors and DPP-4 inhibitors, as the latter comprise
a chemically diverse class of compounds whose

Journal of Hypertension www.jhypertension.com 1297

Cooper et al.

FIGURE 2 Treatment difference in adjusted mean change from baseline in mean 24-h SBP (a), 24-h DBP (b), and heart rate (c) at week 24 by antihypertensive background
therapy. Treatment difference: difference in the adjusted means for linagliptin versus placebo at week 24; yanalysis of covariance model includes baseline mean 24-h SBP,
baseline log10 (urinary albumin-to-creatinine ratio), baseline glycated hemoglobin A1c as linear covariates and treatment as a fixed effect; zanalysis of covariance model
includes baseline mean 24-h SBP, baseline log10 (urinary albumin-to-creatinine ratio), baseline glycated hemoglobin A1c as linear covariates and treatment, angiotensin-
converting enzyme inhibitor/angiotensin II receptor blocker background therapy at baseline, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker back-
ground therapy at baseline by treatment interaction as fixed effects; §analysis of covariance model includes baseline mean 24-h DBP, baseline log10 (urinary albumin-to-
creatinine ratio), baseline glycated hemoglobin A1c as linear covariates and treatment as a fixed effect; analysis of covariance model includes baseline mean 24-h DBP,
baseline log10 (urinary albumin-to-creatinine ratio), baseline glycated hemoglobin A1c as linear covariates and treatment, angiotensin-converting enzyme inhibitor/angioten-
sin II receptor blocker background therapy at baseline, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker background therapy at baseline by treatment
interaction as fixed effects; yyanalysis of covariance model includes baseline mean 24-h heart rate, baseline log10 (urinary albumin-to-creatinine ratio), baseline glycated
hemoglobin A1c as linear covariates and treatment as a fixed effect; zzanalysis of covariance model includes baseline mean 24-h heart rate, baseline log10 (urinary albumin-
to-creatinine ratio), baseline glycated hemoglobin A1c as linear covariates and treatment, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker back-
ground therapy at baseline, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker background therapy at baseline by treatment interaction as fixed
effects. ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; CI, confidence interval.

1298 www.jhypertension.com Volume 37  Number 6  June 2019

 Hemodynamics of linagliptin/renin–angiotensin system blockers

TABLE 2. Adverse events (telmisartan) and linagliptin in a hypertensive diabetic

Linagliptin, Placebo, mouse model [21] and in the 2-kidney 1-clip rat model of
n ¼ 182 n ¼ 178 renovascular hypertension [22]. Both studies showed that
Any adverse event 58.8 60.1
the BP-lowering effect of telmisartan was not affected by
Drug-related adverse event 7.1 6.2 concomitant treatment with linagliptin [21,22].
Adverse event leading to discontinuation 1.6 1.1 Limitations of this study include the fact that treatment
Serious adverse event 9.3 4.5 effects were not evaluated in subgroups based on BMI or
Vascular disordersa 3.8 3.9 eGFR level, due to low patient numbers in certain of
Hypertension 2.2 2.2 these subgroups.
Hypotension 0.5 1.1
In conclusion, this prespecified exploratory analysis of
Aortic occlusion 0.0 0.6
Ischemic necrosis 0.0 0.6
the MARLINA-T2D clinical trial does not support the exis-
Hematoma 0.5 0.0 tence of an adverse hemodynamic interaction between
Orthostatic hypotension 0.5 0.0 DPP-4 inhibitors, in general, and ACE inhibitors or ARBs.
Hypersensitivity reactionsb 4.4 3.4 The lack of an increase in BP or HR observed in our study
Eczema 0.5 1.7 suggests that concomitant use of linagliptin with either ACE
Contact dermatitis 1.1 1.1
inhibitors or ARBs in patients with albuminuric diabetic
Eyelid edema 0.0 0.6
Dermatitis 0.5 0.0
kidney disease is safe in this regard. Taken together with the
Hypersensitivity 0.5 0.0 lack of an increase in cardiovascular events seen in partic-
Rash 0.5 0.0 ipants receiving alogliptin and ACE inhibitors in the EXAM-
Allergic rhinitis 0.5 0.0 INE study [19], our findings suggest that hemodynamic
Face swelling 0.5 0.0 effects arising from the combination of a DPP-4 inhibitor
Cardiovascular eventsc 1.6 0.6 and an ACE inhibitor are either limited to the acute setting
Transient ischemic attack 0.0 0.6
Nonfatal stroke 0.0 0.0
or are not a class effect of DPP-4 inhibitors.
Nonfatal myocardial infarction 0.5 0.0
Hospitalization for unstable angina 0.0 0.0 ACKNOWLEDGEMENTS
Cardiovascular death 1.1 0.0
Acute myocardial infarction 0.0 0.0 The authors thank the participants and staff involved in this
Sudden death 0.0 0.0 study. Medical writing assistance, supported financially by
Worsening of heart failure 0.0 0.0 Boehringer Ingelheim, was provided by Giles Brooke, PhD,
Cardiogenic shock 0.0 0.0
CMPP, of Envision Scientific Solutions during the prepara-
Fatal stroke 0.5 0.0
Ischemic stroke 0.0 0.0
tion of this article.
Hemorrhagic stroke 0.5 0.0 Data from this study have previously been presented at the
Not assessable 0.0 0.0 52nd Annual Meeting of the European Association for the
Other 0.5 0.0 Study ofDiabetes, Munich, Germany,12–16September,2016.
The current study was supported by the Boehringer
Data are % of participants in the treated set (all randomized participants who received at
least one dose of study drug). Medical Dictionary for Regulatory Activities (MedDRA) Ingelheim and Eli Lilly and Company Diabetes Alliance.
version 18.1 used for reporting.
a
System organ class from MedDRA 18.1.
b
c
Standardized MedDRA Query from MedDRA 18.1. Conflicts of interest
Cardiovascular events confirmed after adjudication by an external clinical events
committee. M.E.C., V.P., P.-H.G., and B.H. have received fees for
advisory services to Boehringer Ingelheim. U.H., T.M.,
A.K.-W., S.v.d.W., and M.v.E. are employees of Boehringer
Ingelheim.
pharmacokinetic properties vary substantially [18]. Whereas
the previous studies employed an experimental DPP-4 inhib-
itor, P32/98 [9], and a widely prescribed member of this drug
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Volume 37  Number 6  June 2019